Browsing by Author "Vasan, Soumini"

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    Cascades of genetic instability resulting from compromised break-induced replication
    (2013) Vasan, Soumini; Malkova, Anna; Atkinson, Simon; Kusmierczyk, Andrew
    Break-induced replication (BIR) is a mechanism to repair double-strand breaks (DSBs) that possess only a single end that can find homology in the genome. This situation can result from the collapse of replication forks or telomere erosion. BIR frequently produces various genetic instabilities including mutations, loss of heterozygosity, deletions, duplications, and template switching that can result in copy-number variations (CNVs). An important type of genomic rearrangement specifically linked to BIR is half crossovers (HCs), which result from fusions between parts of recombining chromosomes. Because HC formation produces a fused molecule as well as a broken chromosome fragment, these events could be highly destabilizing. Here I demonstrate that HC formation results from the interruption of BIR caused by a defective replisome or premature onset of mitosis. Additionally, I document the existence of half crossover instability cascades (HCC) that resemble cycles of non-reciprocal translocations (NRTs) previously described in human tumors. I postulate that HCs represent a potent source of genetic destabilization with significant consequences that mimic those observed in human diseases, including cancer.
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    ROLE OF CHECKPOINT PROTEINS IN THE SUCCESS OF BIR
    (Office of the Vice Chancellor for Research, 2012-04-13) Vasan, Soumini; Deem, Angela; Argueso, Lucas; Malkova, Anna
    Break-induced replication (BIR) is an important homologous recombina-tion (HR) pathway employed to repair DNA lesions and has been implicated in various chromosomal instabilities, including loss of heterozygosity, trans-locations, and alternative telomere lengthening. Here, we study the role of checkpoint proteins in DNA repair in yeast Saccharomyces cerevisiae. Cell cycle checkpoints are required for the proper progression of the cell cycle. These checkpoint proteins sense problems during the cell cycle and halt pro-gression to allow mistakes to be corrected and the loss of checkpoint con-trols leads to major defects. RAD9 and RAD24, two important checkpoint proteins play a vital role in arresting the cell cycle upon DNA damage and are also responsible for bringing together the DNA repair machinery. We ob-served that mutations made in the genes encoding RAD9 and RAD24 result-ed in the formation of multiple sectors in individual colonies where, every in-dividual sector repaired differently. We analyze the frequency of different re-pair outcomes associated with BIR in these multi-sectored events. We also report that defective BIR in these checkpoint mutants lead to formation of half-crossovers similar to NRTs reported in mammals, which are implicated in the initiation of cascades of genomic instability characteristic of human cancer cells. 1Department of Environmental and Radiological Health Sciences, College of Veterinary Medi-cine & Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.